CXCR4 and CCR5 ligands cooperate in monocyte and lymphocyte migration and in inhibition of dual-tropic (R5/X4) HIV-1 infection

One of the most important functions of chemokines and their receptors is the regulation of directional migration of leukocytes within tissues. In specific tissue compartments, cells are exposed to multiple chemokines presented in complex dimensional and temporal patterns. Therefore, a leukocyte requires the mechanisms to integrate the various directional signals it receives from different chemoattractants. In this study, we report that CCL3, CCL5, and CCL8, three potent mononuclear cell chemoattractants, are able to synergize with the homeostatic chemokine CXCL12 in the migration of CD14(+) monocytes, CD3(+) T-lymphocytes, or PHA-activated lymphoblasts. In addition, CCL5 augmented the CXCR4 ligand-driven ERK phosphorylation in mononuclear cells. Furthermore, the synergistic effect between CCL5 and CXCL12 in monocyte chemotaxis is inhibited in the presence of specific CCR1 antibody and AMD3100, but not by maraviroc. In HIV-1 infection assays, a combination of CXCL12 and CCL5 cooperated to inhibit the replication of the dual-tropic (R5/X4) HIV-1 HE strain. Finally, although the dual-tropic HIV-1 strain was barely suppressed by AMD3100 or maraviroc alone, HIV-1 infection was completely blocked by the combination of these two receptor antagonists. Our data demonstrate the cooperation between CCL5 and CXCL12, which has implications in migration of monocytes/lymphocytes during inflammation and in HIV-1 infection.